Partial Lipodystrophy and LMNA p.R545H Variant

Abstract

Laminopathies are disorders caused by LMNA gene mutations, which selectively affect different tissues and organ systems, and present with heterogeneous clinical and pathological traits. The molecular mechanisms behind these clinical differences and tissue specificity have not been fully clarified. We herein examine the case of a patient carrying a heterozygous LMNA c.1634G>A (p.R545H) variant with a mild, transient myopathy, who was referred to our center for the suspicion of lipodystrophy. At physical examination, an abnormal distribution of subcutaneous fat was noticed, with fat accumulation in the anterior regions of the neck, resembling the fat distribution pattern of familial partial lipodystrophy type 2 (FPLD2). The R545H missense variant has been found at very low allelic frequency in public databases, and in silico analysis showed that this amino acid substitution is predicted to have a damaging role. Other patients carrying the heterozygous LMNA p.R545H allele have shown a marked clinical heterogeneity in terms of phenotypic body fat distribution and severity of organ system involvement. These findings indicate that the LMNA p.R545H heterozygous variant exhibits incomplete penetrance and highly variable expressivity. We hypothesized that additional genetic factors, epigenetic mechanisms, or environmental triggers might explain the variable expressivity of phenotypes among various patients.

Keywords: FPLD2; LMNA mutation; familial partial lipodystrophy type 2; leptin; lipodystrophy.

Figure 1

Schematic structure of LMNA. In the upper panel, filled boxes indicate the exons of the gene (A). Protein domains are displayed color-coded in the lower panel (B). The heterozygous LMNA variant detected is also reported. NLS, nuclear localisation signal.

Figure 2

Pictures of the patient carrier of the heterozygous LMNA pR545H mutation. (A,B) Anterior and lateral view of the patient taken two years before (at age 17) plastic surgery intervention. Excess of fat over the shoulders and in the anterior regions of the neck along the jawline is evident without clear signs of lipoatrophy. (C) Anterior and lateral view of the patient taken one month after the plastic surgery intervention (liposuction).

Figure 3

Top: Cardiac magnetic resonance four-chamber view showing normal biventricular volumes and wall thickness at cine steady-state free-precession (A) with no apparent areas of fibrosis at late gadolinium enhancement (B). Bottom: Short axis apical view showing a small, non-specific fibrofatty area in the distal interventricular septum appearing dark at cine steady-state free-precession sequences (C) and bright at late enhancement sequences (D).